Protein kinases play important roles in cellular signal pathways that regulate various cell functions such as differentiation, proliferation, migration, and apoptosis. Deregulation of protein kinases is implicated in a number of diseases including cancer. Thus protein kinases are attractive therapeutic targets in cancer treatment.
Epidermal growth factor receptor (EGFR) is a subfamily of four closely related receptor tyrosine kinases: EGFR, HER2, HER3, and HER4. Binding of EGF ligand to the extracellular domain of EGFR leads to activation of the intracellular protein-tyrosine kinase activity. As a result, autophosphorylation of several tyrosine residues in the C-terminal domain of EGFR occurs. (Kamath, S., Buolamwini, J. K., Med. Res. Rev. 2006, 26, 569-594).
Deregulation in the EGFR signaling cascade has been implicated in the development of various cancers such as bladder, breast, colon, and lung cancer. Several EGFR kinase inhibitors, such as Gefitinib and Erlotinib, have been used for treating cancer, particularly Non-Small Cell Lung cancer (NSCLC). However, only 10-20% of the NSCLC patients respond to Gefitinib treatment, mainly due to drug resistance caused by T790M mutation in EGFR kinase. Thus, it is of great interest to develop EGFR kinase inhibitors, especially those which can inhibit activity of EGFR mutants (e.g., the T790M mutant), as anti-cancer drugs.